pulmicort and Drug-Related-Side-Effects-and-Adverse-Reactions

Diarrhea is a common clinical feature of inflammatory bowel diseases and may be accompanied by abdominal pain, urgency, and fecal incontinence. The pathophysiology of diarrhea in these diseases is complex, but defective absorption of salt and water by the inflamed bowel is the most important mechanism involved. In addition to inflammation secondary to the disease, diarrhea may arise from a variety of other conditions. It is important to differentiate the pathophysiologic mechanisms involved in the diarrhea in the individual patient to provide the appropriate therapy. This article reviews microscopic colitis, ulcerative colitis, and Crohn's disease, focusing on diarrhea.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidiarrheals; Bacterial Infections; Biopsy; Bismuth; Blood Cell Count; Blood Chemical Analysis; Body Water; Breath Tests; Budesonide; Cholestyramine Resin; Colitis, Microscopic; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Endoscopy, Gastrointestinal; Feces; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Intestinal Absorption; Intestinal Fistula; Intestinal Mucosa; Intestines; Ion Transport; Malabsorption Syndromes; Medical History Taking; Mesalamine; Organometallic Compounds; Physical Examination; Postoperative Complications; Prednisolone; Salicylates; Sodium; Tumor Necrosis Factor-alpha

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Budesonide; Chemical Phenomena; Chemistry, Physical; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Esterification; Glucocorticoids; Humans; Respiratory System

Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short-term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD.. An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if: (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), potential systemic side effects of corticosteroids, cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity).. Combining budesonide with surfactant for intratracheal administration is a simple intervention that may reduce BPD in extremely preterm infants and translate into health benefits in later childhood. The PLUSS trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants regardless of their initial mode of respiratory support. Should intratracheal budesonide mixed with surfactant increase survival free of BPD, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice.. Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au ), ACTRN12617000322336. First registered on 28th February 2017.

Topics: Australia; Bronchopulmonary Dysplasia; Budesonide; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Humans; Infant; Infant, Extremely Premature; Infant, Newborn; Multicenter Studies as Topic; Pulmonary Surfactants; Randomized Controlled Trials as Topic; Surface-Active Agents

Although proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. We conducted a randomized phase 2 trial to determine the efficacy and safety of 2 doses of a budesonide suppository vs mesalamine suppositories vs combined budesonide and mesalamine suppositories for proctitis.. We performed a prospective, double-blind, double-dummy, multicenter trial in 337 patients with active proctitis to compare the efficacies of 4 different suppository treatments. Patients were randomly assigned to groups given 2 mg budesonide suppositories (2 mg BUS; n = 89 patients), 4 mg BUS (n = 79), 1 g mesalamine suppositories (1 g MES; n = 81), or the combination of 2 mg BUS and 1 g MES (n = 88). The study was performed from November 2013 through July 2015 at 36 study sites in Europe and Russia. The primary end point was the time to resolution of clinical symptoms, defined as the first of 3 consecutive days with a score of 0 for rectal bleeding and stool frequency.. The mean time to resolution of symptoms in the 4 mg BUS (29.8 days) and combination of 2 mg BUS and 1 g MES (29.3 days) groups resembled that of the standard 1 g MES treatment (29.2 days), but was significantly longer in the 2 mg BUS group (35.5 days). Furthermore, proportions of patients with deep, clinical, and endoscopic remission, as well as mucosal healing, were similar among the 1 g MES, 4 mg BUS, and combination therapy groups, but significantly lower in the group that received 2 mg BUS. No safety signals were observed, and the patients' treatment acceptance was high (67%-85% of patients).. In a multicenter randomized trial, we found that the efficacy and safety of 4 mg BUS in treatment of active proctitis did not differ significantly from those of 1 g MES. Budesonide suppositories offer an alternative therapy to mesalamine for topical treatment of proctitis. Clinicaltrialsregister.eu no: 2012-003362-41.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents; Budesonide; Colitis, Ulcerative; Double-Blind Method; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Humans; Male; Mesalamine; Middle Aged; Proctitis; Prospective Studies; Russia; Suppositories; Treatment Outcome; Young Adult

We aimed to determine the safety and efficacy of budesonide oral suspension (BOS) maintenance therapy in patients with eosinophilic esophagitis (EoE).. We performed an open-label extension study of a 12-week, multicenter, randomized, double-blind, placebo-controlled trial. Patients with EoE (11-40 years old) who completed double-blind BOS (n = 45) or placebo therapy (n = 37) received 24 weeks' open-label BOS (2.0 mg once daily for 12 weeks, with optional dose increase [1.5-2.0 mg twice daily] for 12 weeks thereafter). Predefined efficacy outcomes included: proportion of patients with a histologic response (≤6 eosinophils/high-power field [eos/hpf]) and change in mean peak eosinophil counts after 24 weeks. Analyses were stratified by patients who received placebo (placebo/BOS) or BOS (BOS/BOS) during the double-blind trial.. BOS was well tolerated and drug-related adverse events were uncommon (placebo/BOS, 19% [7/37]; BOS/BOS, 4% [2/45]). Incidence of oral candidiasis (1 per group) and esophageal candidiasis (placebo/BOS group, n = 4) remained low. Changes in morning serum cortisol levels were not clinically relevant. A histologic response was observed in 49% (16/33) of patients receiving placebo/BOS and 23% (9/39) receiving BOS/BOS. Mean peak eosinophil counts (baseline vs week 24 or early termination) were: placebo/BOS, 118.8 vs 29.1; P < .001 and BOS/BOS, 38.1 vs 72.4; P = .01. Of the patients who responded to double-blind therapy, 42% maintained a histologic response during the open-label extension; 4% of nonresponders gained response.. In an open-label extension study of patients with EoE, BOS was well tolerated and drug-related adverse events were uncommon. BOS maintained a histologic response in some initial responders, but few initial nonresponders had a response. ClinicalTrials.gov no: NCT01642212.

Topics: Adolescent; Adult; Animals; Anti-Inflammatory Agents; Budesonide; Child; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Eosinophilic Esophagitis; Female; Humans; Maintenance Chemotherapy; Male; Placebos; Treatment Outcome; Young Adult

No treatment has been approved by the U.S. Food and Drug Administration for eosinophilic esophagitis (EoE). We investigated the efficacy and safety of a new formulation of oral budesonide suspension (OBS), a corticosteroid, in a prospective, placebo-controlled, dose-ranging study.. Subjects 2-18 years old with symptoms of EoE and peak eosinophil counts ≥20/high-power field at ≥2 levels of the esophagus were randomly assigned to groups given placebo or low-dose, medium-dose, or high-dose OBS for 12 weeks. Doses and volumes were adjusted on the basis of patients' age to cover the entire esophagus. The primary efficacy end point was compound response to therapy (peak eosinophil counts ≤6/high-power field at all levels of the esophagus and ≥50% reduction in EoE symptom score). Multiple safety parameters were evaluated.. Data from 71 subjects who completed all efficacy assessments were included in the primary efficacy analysis. At the end of 12 weeks, there were significantly greater percentages of responders in groups given medium-dose OBS (52.6%, P = .0092) and high-dose OBS (47.1%, P = .0174) than in the group given placebo (5.6%); there was no significant difference in percentages of responders between the low-dose OBS (11.8%) and placebo groups (P = .5282). The significant compound responses noted in the medium-dose and high-dose OBS groups were accounted for by the significant histologic responses; in contrast, all 4 groups (including the placebo group) had large symptom responses, and there was no significant difference in the percentage of subjects with a symptom response in either OBS group compared with the placebo group (P ≥ .1235). There were no unexpected safety concerns or signals.. Peak eosinophil counts were significantly reduced throughout the esophagus in pediatric patients with EoE who were given medium-dose and high-dose OBS. There was a large symptom response to placebo that was similar to symptom responses in the OBS groups; symptom response did not distinguish OBS from placebo. ClinicalTrials.gov number, NCT00762073.

Topics: Adolescent; Anti-Inflammatory Agents; Budesonide; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Eosinophilic Esophagitis; Eosinophils; Esophagus; Female; Histocytochemistry; Humans; Leukocyte Count; Male; Suspensions; Treatment Outcome; United States

Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our

Topics: Animals; Budesonide; Colitis; Drug-Related Side Effects and Adverse Reactions; Inflammatory Bowel Diseases; Linoleic Acid; Liposomes; Mice; Prodrugs

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Bronchodilator Agents; Budesonide; Child; Child, Preschool; Comorbidity; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Prevalence; Risk Factors; Treatment Outcome; Young Adult

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Adverse drug reactions is an important healthcare issue, it causes excess morbidity and mortality. The aim of this study was to determine the adverse drug reactions in patients who admitted to the outpatient clinic of respiratory diseases and to improve some clinical strategies if they are preventable.. This study is a prospective observational study which was performed to determine adverse drug reaction in patients who admitted to the outpatient clinic of respiratory diseases.. During the 15 months of study period a total of 114 adverse reactions were reported in 92 out of 18.130 patients. Most of the adverse reactions were related with gastrointestinal system, central nervous system and cardiovascular system. The most of the adverse events were associated with fixed inhaled formoterol-budesonide combination and inhaled tiotropium. The most frequently reported reactions were hoarseness, xerostomia, headache and dizziness. Poliuri and cough were less frequently reported reactions.. Most of the adverse reactions were of limited intensity but some of these side effects might effect patients compliance. Serious adverse events were not detected.

Topics: Administration, Inhalation; Bronchodilator Agents; Budesonide; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Ethanolamines; Female; Formoterol Fumarate; Humans; Male; Middle Aged; Outpatient Clinics, Hospital; Patient Compliance; Pharmacovigilance; Respiratory Tract Diseases; Scopolamine Derivatives; Tiotropium Bromide

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Topics: Administration, Inhalation; Adolescent; Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Asthma; Body Height; Budesonide; Child; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Humans; Long-Term Care

The chemical space of registered oral drugs was explored for inhibitors of the human multidrug-resistance associated protein 2 (MRP2; ABCC2), using a data set of 191 structurally diverse drugs and drug-like compounds. The data set included a new reference set of 75 compounds, for studies of hepatic drug interactions with transport proteins, CYP enzymes, and compounds associated with liver toxicity. The inhibition of MRP2-mediated transport of estradiol-17beta-D-glucuronide was studied in inverted membrane vesicles from Sf9 cells overexpressing human MRP2. A total of 27 previously unknown MRP2 inhibitors were identified, and the results indicate an overlapping but narrower inhibitor space for MRP2 compared with the two other major ABC efflux transporters P-gp (ABCB1) and BCRP (ABCG2). In addition, 13 compounds were shown to stimulate the transport of estradiol-17beta-D-glucuronide. The experimental results were used to develop a computational model able to discriminate inhibitors from noninhibitors according to their molecular structure, resulting in a predictive power of 86% for the training set and 72% for the test set. The inhibitors were in general larger and more lipophilic and presented a higher aromaticity than the noninhibitors. The developed computational model is applicable in an early stage of the drug discovery process and is proposed as a tool for prediction of MRP2-mediated hepatic drug interactions and toxicity.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antipsychotic Agents; Antiviral Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Cell Line; Computer Simulation; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Estradiol; Humans; Insecta; Liver; Models, Molecular; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Pharmaceutical Preparations; Pharmacology; Structure-Activity Relationship

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration